Development of a cancer cells self-activating and miR-125a-5p expressing poly-pharmacological nanodrug for cancer treatment

Yung Chieh Chang, Min Chieh Shieh, Yen Hsuan Chang, Wei Lun Huang, Wu Chou Su, Fong Yu Cheng, Chun Hei Antonio Cheung

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their down- stream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing poly-pharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a-5p (miR-125a-5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the anti-apoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoter-driven, miR-125a-5p expressing, poly-L-lysine-conjugated magnetite iron poly-pharmacologic nanodrug (pL-MNP-pSur-125a) was reported. The cancer cells self-activating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1-expressing/-non-expressing cancer cells invitroandinvivo.ItwasdemonstratedthatpL-MNP-pSur-125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pL-MNP-pSur-125a also downregulated the expres- sion of TDO2 in the human KB cervical carcinoma cells. PL-MNP-pSur-125a decreased the viability of various BIRC5-expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5-non-expressing HMEC-1 endothelial cells. In vivo, pL-MNP-pSur-125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish human-ABCB1-expressing and ABCB1-non-expressing tumor xenograft models. In conclusion, pL-MNP-pSur-125a is an easy-to-prepare and a promising poly-pharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1-related drug resistance after prolonged chemotherapeutic treatments.

Original languageEnglish
Article number102
JournalInternational journal of molecular medicine
Volume50
Issue number2
DOIs
Publication statusPublished - 2022 Aug

All Science Journal Classification (ASJC) codes

  • Genetics

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